Osteoporosis is recognized has a major public health problem in the USA today, with the likelihood of increased societal impact as "baby boomers" age. Therapeutic options are currently limited to "anti-resorptive" therapies which reduce bone turnover. Therapeutic options are currently limited to "anti-resorptive" therapies which reduce bone turnover, stabilize bone mass and reduce but not eliminate fracture risk, in part because many treated individuals are left with a bone mass that remains less than optimal. Thus, there is a clear need for agents that stimulate new bone formation. Our Specialized Center of Research has assembled a panoply of basic and clinical scientists to focus on this issue. Over the past 9 years we have investigated interactions of parathyroid hormone and sex steroids in the development and treatment of osteoporosis. Our cohesive and integrated approach has generated a significant base of knowledge, culminating in the demonstration that PTH (superimposed on standard HRT) not only increases bone mass but may also reduce vertebral fracture risk. In our current application, in four inter-related and integrated projects, we will examine aspects of PTH action at both basic and clinical levels. In Project 1 we will use novel techniques to isolate functional human osteoclasts and transgenic murine models to examine the mechanisms underlying osteoclast differentiation and death. In Project 2 the ovariectomized rat model will be used to evaluate morphological, biochemical, and mechanical responses to PTH, comparing a model of primary hyperparathyroidism (continuous PTH infusion) with intermittent PTH administration, in both estrogen replete and depleted states. The next project uses the paradigm of endogenous primary hyperparathyroidism in post-menopausal women to characterize the effects of chronically increased PTH, and its reduction (after parathyroidectomy) on skeletal homeostasis. The last project focusses on the mechanism underlying the initial period of new bone formation that occurs in the early months of PTH therapy, as well as the effects of withdrawal of treatment. Each of these projects relies heavily on the support of "Core" units,: Administration/Statistics; Biochemistry; Histomorphometry; and Bone Mass Measurement, with integration of all Projects and Cores with regard to protocols, investigators and data interpretation.